Heinz Heimgartner

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 1,3‐Selenazoles from N‐Phenylimidoyl Isoselenocyanates

The reaction of N-phenylbenzamides 5 with excess SOCl2 under reflux gave N-phenylbenzimidoyl chlorides 6, which, on treatment with KSeCN in acetone, yielded imidoyl isoselenocyanates of type 2. These products, obtained in almost quantitative yield, were stable in the crystalline state. They were transformed into selenourea derivatives 7 by the reaction with NH3, or primary or secondary amines. In acetone at room temperature, 7 reacted with activated bromomethylene compounds such as 2-bromoacetates, acetamides, and acetonitriles, as well as phenacyl bromides and 4-cyanobenzyl bromide to give 1,3-selenazol-2-amines of type 9 (Scheme 2). A reaction mechanism via alkylation of the Se-atom of 7, followed by ring closure and elimination of aniline, is most likely (cf. Scheme 7). In the case of selenourea derivatives 7d and 7l with an unsubstituted NH2 group, an alternative ring closure via elimination of H2O led to 1,3-selenazoles 10a and 10b, respectively (Schemes 4 and 7). On treatment with NaOH, ethyl 1,3-selenazole-5-carboxylates 9l and 9s were saponified and decarboxylated to give the corresponding 5-unsubstituted 1,3-selenazoles 12a and 12b (Scheme 6). The molecular structures of selenourea 7f and the 1,3-selenazoles 9c and 9d have been established by X-ray crystallography (Figs. 1 and 3).

Addition of carboxylic acids and cyclic 1,3-diketones to 2-dimethylamino-3,3-dimethyl-1-azirine

Abstract The reaction of 2 - dimethylamino - 3,3 - dimethyl - 1 - azirine 1 with carboxylic acids 2a-e at room temperature in inert solvents generates rearranged 1:1 adducts in 65–92% yields. These adducts are N-acyl derivatives of 2-amino, -N,N dimethyl-isobutyramide 3a-e resulting from 1,2 addition of the acid followed by 1,2 ring cleavage and transfer of an acyl group. Cyclic enolizable 1,3 diketones 4a-c react similarly with 1 to yield the corresponding rearranged 1:1 adducts 5a-c, whereas acyclic diketones or ethyl acetoacetate are inert under comparable experimental conditions.

Site-selective incorporation of thioamide-linkages into a growing peptide

Abstract The use of endothiodipeptide anilides, which were obtained in high yields by a variation of the ‘azirine/oxazolone method’, for the synthesis of longer endothiopeptides is described. With this novel methodology, epimerically pure endothiopeptides with the thiocarbonyl group next to the bulky Aib were prepared in satisfactory yields. The structures of two endothiotripeptides and one endothiotetrapeptide were established by single-crystal X-ray crystallography.

Selenium-Containing Heterocycles from Isoselenocyanates: Synthesis of 1,2,3-Selenadiazole Derivatives

The reaction of aroyl chlorides 1 with KSeCN and ethyl diazoacetate (6) in acetone at room temperature yields ethyl 2-aroyl-5-(aroylimino)-2,5-dihydro-1,2,3-selenadiazole-4-carboxylates 7 (Scheme 3). A reaction mechanism via the initial formation of the corresponding aroyl isoselenocyanates 2 followed by a 1,3-dipolar cycloaddition of the diazo compound with the C=Se bond to give ethyl 5-(aroylimino)-4,5-dihydro-1,2,3-selenadiazole-4-carboxylates of type D is proposed. Acylation of the latter at N(2) leads to the final products 7. Deacetylation of 7 to give ethyl 5-(aroylimino)-1,2,3-selenadiazole-4-carboxylates 10 is achieved by treatment of 7 with morpholine (Scheme 5). The intermediate isoselenocyanates 2 partially oligomerize to give two different oligomers. The symmetrical one reacts with morpholine to yield selenourea derivatives 12 (Scheme 6).

Synthesis of the endothiopeptide BOC-Trp-Ile-Ala-Aib-Ile-ValΨ[CSNH]Aib-Leu-Aib-Pro-OMe by a variation of the ‘azirine/oxazolone method’

Abstract The synthesis of the decaendothiopeptide BOC-Trp-Ile-Ala-Aib-Ile-ValΨ[CSNH]Aib-Leu-Aib-Pro-OMe is described. The introduction of the thioamide group next to the bulky Aib occurred via a variation of the ‘azirine/oxazolone method’ without epimerisation. The structure of the decaendothiopeptide was etablished by single-crystal X-ray crystallography, thereby two types of helices could be observed.

Synthesis of Bis(2,4-diarylimidazol-5-yl) Diselenides from N-Benzylbenzimidoyl Isoselenocyanates

The reaction of N-benzylbenzamides 6 with SOCl2 under reflux gave the corresponding N-benzylbenzimidoyl chlorides 7. Further treatment with KSeCN in dry acetone yielded imidoyl isoselenocyanates 3 (Scheme 2). These compounds, obtained in satisfying yields, proved to be stable enough to be purified and analyzed. Reaction of 3 with morpholine in dry acetone led to the corresponding selenourea derivatives 8. On treatment with Et3N, the 4-nitrobenzyl derivatives of type 3 were transformed into bis(2,4-diarylimidazol-5-yl) diselenides 9 (Scheme 3). This transformation takes place only when the benzyl residue bears an NO2 group and the phenyl group is not substituted with a strong electron-donating group. A reaction mechanism for the formation of 9 is proposed in Scheme 4. The key structures have been established by X-ray crystallography.

Isoselenocyanates as Building Blocks for Selenium-Containing Heterocycles

Isoselenocyanates are conveniently accessible from elemental selenium in safe and efficient reactions. They can be used either as reactive intermediates or as relatively stable and storable starting materials for the preparation of selenaheterocycles or heterocyclic selones. In most cases, the reactions are initiated by a nucleophilic attack onto the isoselenocyanate, followed by a cyclization via the Se-or the N-atom. Alternatively, the intermediate adduct of the nucleophile and the isoselenocyanate can undergo a second nucleophilic addition with a third compound and subsequent cyclization.

Synthesis of Imidazole Derivatives Using 2‐Unsubstituted 1H‐Imidazole 3‐Oxides

The reaction of 1,4,5-trisubstituted 1H-imidazole 3-oxides 1 with Ac2O in CH2Cl2 at 0 - 5° leads to the corresponding 1,3-dihydro-2H-imidazol-2-ones 4 in good yields. In refluxing Ac2O, the N-oxides 1 are transformed to N-acetylated 1,3-dihydro-2H-imidazol-2-ones 5. The proposed mechanisms for these reactions are analogous to those for N-oxides of 6-membered heterocycles (Scheme 2). A smooth synthesis of 1H-imidazole-2-carbonitriles 2 starting with 1 is achieved by treatment with trimethylsilanecarbonitrile (Me3SiCN) in CH2Cl2 at 0 - 5° (Scheme 3).

Synthesis of conformationally restricted cyclic pentadepsipeptides via direct amide cyclization

Abstract The 2,2-disubstituted 2H-azirin-3-amines 6 (3-amino-2H-azirines) were used as building blocks for α,α-disubstituted α-amino acids in the preparation of 16-membered cyclic depsipeptides 14. The linear precursors containing four α,α-disubstituted α-amino acids, the pentapeptides 13, were synthesized starting with β-hydroxy acids 5 via the ‘azirine/oxazolone method’. The cyclic depsipeptides 14 were formed via ‘direct amide cyclization’ and the influence of several factors on this cyclization was investigated in the following way: (a) using the same composition of α,α-disubstituted α-amino acids, but changing their respective positions in the peptide chain; (b) using different C-terminal α,α-disubstituted α-amino acids in the peptide chain; (c) using different β-hydroxy acids; and (d) using different diastereoisomers of the peptides.

Reactions of 2-Unsubstituted 1 H -Imidazole 3-Oxides with Heterocumulenes and Dimethyl Acetylenedicarboxylate

Reaction of 2-unsubstituted 1H-imidazole 3-oxides with isocyanates, isothiocyanates, and dimethyl acetylenedicarboxylate led to the formation of 2-functionalized imidazole derivatives. Stepwise reaction mechanisms via zwitterionic intermediates are proposed. The intermediate [3+2] cycloadducts stabilize via extrusion of COX or ring opening.